Cyclin-dependent kinases (CDKs) are a family of serine/threonine kinases that regulate key cellular processes including cell cycle progression and RNA transcription (Shapiro G I. J Clin Oncol. 2006 Apr. 10; 24(11):1770-83). Heterodimerized with regulatory cyclin units, CDKs can be generally divided into two groups based on their functions. The first group consists of core cell cycle components and governs the cell cycle transition and cell division: cyclin D-dependent kinases 4/6 and cyclin E-dependent kinase 2, which control the G1→S transition; cyclin A-dependent kinases 1/2, a critical regulator of S-phase progression; cyclin B-dependent CDK1, required for the G2→M transition; and cyclin H/CDK7, the CDK-activating kinase. The second group, so called transcriptional CDKs, includes cyclin H/CDK7 and cyclin T/CDK9 which phosphorylate the C-terminal domain (CTD) of RNA polymerase II and promote transcriptional initiation and elongation.
The deregulation of the CDK activity is detected in virtually all forms of human cancer, most frequently due to the overexpression of cyclins and loss of expression of CDK inhibitors (de Cárcer G et al., Curr Med. Chem. 2007; 14(9):969-85). CDK4/6 inhibition has been shown to induce potent G1 arrest in vitro and tumor regression in vivo (Lukas J et al., Nature. 1995 Jun. 8; 375(6531):503-6; Schreiber M et al., Oncogene. 1999 Mar. 4; 18(9):1663-76; Fry D W et al., Mol Cancer Ther. 2004 November; 3(11):1427-38). Various approaches aimed at targeting CDK2/1 have been reported to induce S and G2 arrest followed by apoptosis (Chen Y N et al., Proc Natl Acad Sci USA. 1999 Apr. 13; 96(8):4325-9; Chen W et al., Cancer Res. 2004 Jun. 1; 64(11):3949-57; Mendoza N et al., Cancer Res. 2003 Mar. 1; 63(5):1020-4). Inhibition of the transcriptional CDKs 7 and 9 can affect the accumulation of transcripts encoding anti-apoptosis family members, cell cycle regulators, as well as p53 and NF-κB-responsive gene targets (Lam L T et al., Genome Biol. 2001; 2(10):RESEARCH0041). All these effects contribute to the induction of apoptosis and also potentiation of cytotoxicity mediated by disruption of a variety of pathways in many cancer cell types (Chen R et al., Blood. 2005 Oct. 1; 106(7):2513-9; Pepper C et al., Leuk Lymphoma. 2003 February; 44(2):337-42). CDKs are therefore recognized as an attractive target for the design and development of compounds that can specifically bind and inhibit the cyclin-dependent kinase activity and its signal transduction pathway in cancer cells, and thus can serve as either diagnostic or therapeutic agents. For example, the potent and highly selective CDK2/1 inhibitor, SNS-032 (BMS-387032), and the CDK4/6 inhibitor, PD 332991, are currently in clinical trials for treatment of cancer.
Numerous reports have indicated that CDK inhibitors may be therapeutically effective in several other disease indications than cancer, including polycystic kidney disease (Ibraghimov-Beskrovnaya O, Cell Cycle. 2007, 6:776-9), mesangial proliferative glomerulonephritis, crescentic glomerulonephritis, proliferative lupus nephritis, collapsing glomerulopathy, IgA nephropathy (Soos T J et al., Drug News Perspect. 2006, 19:325-8) and Alzheimer's disease (Monaco E A & Vallano M L. Front Biosci. 2005, 10:143-59). CDKs are required for replication of many viruses such as human cytomegalovirus, herpes simplex virus type 1 and HIV-1. Specific pharmacological CDK inhibitors have demonstrated broad antiviral activities (Schang L M et al., Antivir Chem. Chemother. 2006; 17(6):293-320; Pumfery A et al., Curr Pharm Des. 2006; 12(16):1949-61). Given the mounting evidence for the role of CDK activity in a variety of disease states, there is a need for new inhibitors of CDK activity.